Contribution of chloride channels to the action potential and contraction in human myometrium during labour.

Background And Purpose: The action potential underpinning calcium delivery for contraction in human uterine smooth muscle (myometrium) consists of an initial spike(s) followed by a prolonged plateau of depolarization to ⁓ -25 mV. The plateau duration establishes contraction duration, especially important in labour. The purpose of this study was to determine the role of ANO1/TMEM16A chloride channels in the plateau.

Experimental Approach: Term human myometrial strips were obtained immediately following elective caesarean delivery before labour and during normally progressing labour. Contraction was recorded simultaneously with intracellular microelectrode recording of membrane potential. The chloride channel ANO1/TMEM16A was blocked using CaCC (5 𝜇M). Channel expression was probed via Western blotting.

Key Results: Myometrial strips were spontaneously contractile. The initial action potential spike(s) reflect the opening of voltage-gated calcium channels, since they were blocked by verapamil. The plateau, at -20 to 35 mV, had durations of 0.4 min before and 1.6 min during labour. CaCC abolished the plateau and markedly reduced contraction amplitude and duration. CaCC also reduced the ability of oxytocin, a vital labour hormone, to augment contraction. Western blotting revealed that myometrial ANO1 expression doubles in normal human labour.

Conclusion And Implications: The ANO1/TMEM16A chloride conductance 'clamps' the human myometrial membrane potential at a depolarized plateau, extending calcium influx and prolonging contraction, including that evoked by oxytocin. This function of ANO1 and its enhanced expression in labour are likely critical for the large and prolonged contractions required for expeditious birth of the offspring.